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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901065v1 183/6/4119    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Wang, J. Articles by Toes, R. E. M. PubMed PubMed Citation Articles by Wang, J. Articles by Toes, R. E. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB TRANS-RETINOIC ACID

De Novo Generation and Enhanced Suppression of Human CD4⁺CD25⁺ Regulatory T Cells by Retinoic Acid¹

Department of Rheumatology C1-R, Leiden University Medical Center, Leiden, The Netherlands

Therapies based on CD4⁺CD25⁺FOXP3⁺ T regulatory (Treg) cells offer promise for the restoration of tolerance in many immune-mediated disorders. However, it has been proven difficult to obtain large numbers of Treg cells with potent and stable suppressive ability from adult human peripheral blood because of the lack of specific markers for Treg isolation/characterization, compromised function of isolated CD4⁺CD25^+/+ T cell populations, and the difficulty to convert conventional T cells, for example, by TGF-β, into Treg cells in a consistent manner. In this study, we show that 1) in the presence of TGF-β, all-trans-retinoic acid (ATRA) efficiently converts adult human peripheral blood naive CD4⁺ T cells into FOXP3⁺ Treg cells with stable and potent suppressive ability; 2) memory CD4⁺ T cells are resistant to FOXP3 induction and, moreover, inhibit Treg conversion of naive T cells that can be partially reversed by anti-IL-4; and 3) treatment of isolated CD4⁺CD25^+/+ T cells with ATRA/TGF-β enhances their suppressive potential during expansion. Our results indicate that ATRA/TGF-β can be used to generate highly suppressive CD4⁺FOXP3⁺ Treg cells from adult human peripheral blood and are relevant for the development for Treg-based therapies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the European Community’s FP6 funding Project 018661 Autocure and FP7 Project HEALTH-F2-2007-2.4.5-12 Masterswitch, the Dutch Arthritis Foundation (Grant 0801021), and the Netherlands Organization for Scientific Research VIDI and VICI grant (to R.E.M.T.).

² Address correspondence and reprint requests to Jun Wang or Dr. Rene E. M. Toes, Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. E-mail address: J.Wang{at}lumc.nl or R.E.M.Toes{at}lumc.nl

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ T regulatory; ATRA, all-trans-retinoic acid.

⁴ The online version of this article contains supplemental material.